Respiratory Cell & Molecular Biology
The overarching theme of the research in this group is the investigation of the molecular mechanisms underlying chronic inflammation in severe asthma and COPD and how these processes are affected by oxidative stress and by corticosteroids. These studies are performed in both cultured and primary airway structural cells (epithelial cells and smooth muscle cells), T-cells and monocytes/macrophages, in human lung tissues and in animal models of disease. As a group we use molecular, pharmacological and histological techniques including reporter gene assays, overexpression, Western blotting, RT-qPCR, confocal imaging, chromatin immunoprecipitation, 3C analysis, transcriptomic analysis, SILAC/iTRAQ and siRNA. There is a major focus on translational research with the application of state-of-the-art molecular techniques to primary cells from patients with airways disease. We work closely with colleagues within other groups in Airways Disease such as Professor Chung (Severe Asthma), Professors Barnes and Donnelly (COPD) and Dr Usmani (Small Airways) to enable better translational research. We also collaborate with other researchers within NHLI to examine inflammatory responses to infections (Professor Johnston), in pulmonary hypertension (Dr Wort), in fibrosis (Dr Renzoni) and following heart surgery (Professor Angelini).
We also collaborate with Professors Chung and Belvisi examining animal models of severe asthma and COPD. We have an increasing interest in the mechanisms by which patients with COPD have an enhanced risk of lung cancer. We have an ongoing collaboration with the Department of Computing at IC to enable integration of complex data sets and disease modelling (Professor Guo) as part of UBIOPRED using the eTRIKs platform. A demonstration of the use of the TransMART platform to analyse U-BIOPRED data is provided at the following link (Watch 'tranSMART training' | Microsoft Stream). Mathematical modelling of signalling pathways that cross-talk with corticosteroids is also an area of interest (Professors Guo and Chung). We are currently also working with Professors Polkey and Chung on mitochondrial dysfunction in COPD as part of COPD-MAP.
Specific ongoing projects include:
- to investigate the role of chromatin modifications and remodelling on inflammatory gene expression in primary airway and vascular structural cells and in airway macrophages.
- to examine the effects of cellular and mitochondrial oxidative stress on airway cell function in vitro, ex vivo and in vivo.
- to determine the effect of acute and chronic rhinovirus infection on inflammation and steroid responsiveness in primary airway cells.
- to develop novel in vivo models of severe asthma.
- to explore cross-talk between GR and other transcription factors and co-regulators in the regulation of immunomodulatory genes in T-cells, macrophages and airway structural cells.
- to perform functional genomics on genes associated with COPD and severe asthma.
to elucidate the mechanisms of MIF actions in COPD.
- to determine the effect of non-coding RNAs on lung inflammation.
- elucidate the effect of carbonyl modification of self proteins on auto-immunity in COPD and in disease models.
The group is funded by the MRC, Wellcome Trust, BBSRC, EU-IMI, Imperial College, the Research Councils UK and by several pharmaceutical companies.
GR nuclear translocation in (a) normal, (b) steroid-sensitive asthma and (c) steroid-resistant asthma patients
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Mallia P et al., Rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012 Dec 1;186(11):1117-24. doi: 10.1164/rccm.201205-0806OC.
Tomita K et al., STAT6 expression in T cells, alveolar macrophages and bronchial biopsies of normal and asthmatic subjects. J Inflamm (Lond). 2012 Mar 9;9:5. doi: 10.1186/1476-9255-9-5.
Yao X et al., Coordinated regulation of IL-4 and IL-13 expression in human T cells: 3C analysis for DNA looping. Biochem Biophys Res Commun. 2012; 417(3):996-1001. doi: 10.1016/j.bbrc.2011.12.069.
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Caramori G et al., Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax. 2011 Jun;66(6):521-7. doi: 10.1136/thx.2010.156448.
Triantaphyllopoulos K et al., A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice. Am J Physiol Lung Cell Mol Physiol. 2011; 300(5):L691-700. doi: 10.1152/ajplung.00252.2010.
Sorrentino R et al., B cells contribute to the antitumor activity of CpG-oligodeoxynucleotide in a mouse model of metastatic lung carcinoma. Am J Respir Crit Care Med. 2011 May 15;183(10):1369-79. doi: 10.1164/rccm.201010-1738OC.
Price LC et al., Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats. Eur Respir J. 2011; 37:813-22. doi:10.1183/09031936.00028310.
Professor Phil HasbroProfessor Daryl Knight, University of Newcastle, NSW, 2012 - 2016
Dr Brian Oliver, University of Sydney, NSW, 2011 - 2015
Dr Xin Yao, Nanjing University, 2007 - 2015